1-Benzenesulfonyl pyrrolidine derivatives as bradykinin receptor antagonists

ABSTRACT

This invention relates to compounds of the formula                    
     where X is halogen, R 1  is H or a C 1 -C 3  alkyl, R 2  is H or OH and R 3  is one of                    
     in which A is a single bond or a —CO(CH 2 ) p —NH— group, R 4  is H or —C(═NR 5 )NHR′ 5 , R 5  and R′ 5  are each H or a C 1 -C 6  alkyl group, R 6  is H or a C 1 -C 3  alkyl group, m is 0, 1 or 2; n is 2, 3 or 4; p is 1, 2 or 3; plus their acid addition salts. The invention likewise relates to the method for their preparation and their therapeutic applications.

This is a 371 of PCT/FR96/02066 filed Dec. 23, 1996.

FIELD OF THE INVENTION

The present invention relates to novel compounds belonging to the benzenesulfonamide family and more particularly to 1-benzenesulfonylpyrrolidine compounds, to the process for their preparation and to their use in therapeutics.

In particular, these novel compounds have an antagonistic action on the bradykinin B₂ receptor and are useful in therapeutics, especially for the treatment of pain, inflammation, asthma and allergic rhinitis.

PRIOR ART

It is known that one of the possible treatments for certain pathological conditions of a painful and/or inflammatory nature (such as asthma, rhinitis, septic shock, toothache, etc.) is to inhibit the action of certain hormones such as bradykinin or kallidin. These peptide hormones are in fact involved in a large number of physiological processes, some of which are closely associated with these pathological conditions.

Although no product possessing this mode of action has yet been marketed, numerous studies have been undertaken in order to create compounds capable of antagonizing the bradykinin receptors. Bradykinin is a peptide hormone consisting of 9 amino acids (Arg—Pro—Pro—Gly—Phe—Ser—Pro—Phe—Arg) and kallidin is a peptide hormone (Lys—Arg—Pro—Pro—Gly—Phe—Ser—Pro—Phe—Arg) which contains an additional amino acid (Lys) compared with bradykinin. It is known that earlier studies made it possible to obtain peptides which interact with the bradykinin receptors: some of them, like bradycor (CP.0127 from Cortech), icatibant (HOE 140 from Hoechst) [“bradycor” and “icatibant” are international non-proprietary names (INN)] or NPC 17761 (from Scios-Nova), have an inhibitory action on the binding of bradykinin to the bradykinin B₂ receptor. More recently, non-peptide compounds have been proposed as antagonists towards the binding of bradykinin to its B₂ receptor, especially in published patent applications EP-A-0596406 and EP-A-0622361. It is also known that certain compounds which are structurally related to the compounds referred to in the two patent applications cited above have already been described for their possible antithrombotic properties, especially in DE-A-3617183 and EP-A-0261539.

OBJECT OF THE INVENTION

There is a need for reducing or eliminating pain and inflammation in mammals and particularly in man.

To meet this need, a novel technical solution has been sought which is effective on the one hand in the treatment of pain, irrespective of its origin, especially pain associated with inflammatory phenomena, and on the other hand in the treatment of inflammation.

According to the invention, it is proposed to provide a novel technical solution which involves competitive binding, at the bradykinin B₂ receptor, between (i) bradykinin and related or analogous hormones such as kallidin, and (ii) an antagonist, and utilizes benzenesulfonamide compounds which are structurally different from the known products mentioned above and which limit or substantially inhibit the binding of bradykinin and said analogous hormones to said bradykinin B₂ receptor.

In accordance with this novel technical solution, it is proposed according to a first aspect of the invention to provide benzenesulfonamide compounds as novel industrial products, according to a second aspect of the invention to provide a process for the preparation of these compounds, and according to a third aspect of the invention to provide the use of these compounds, especially in therapeutics, as analgesic and/or anti-inflammatory active ingredients.

SUBJECT OF THE INVENTION

In accordance with the novel technical solution of the invention, a benzenesulfonylpyrrolidine compound is recommended as a novel industrial product, said compound being characterized in that it is selected from the group consisting of:

(i) the compounds of the formula

in which:

X is a halogen atom,

R₁ is a hydrogen atom or a linear or branched C₁-C₃ alkyl group,

R₂ is a hydrogen atom or an OH group,

R₃ is a group

A is a single bond or a group —CO—(CH₂)_(p)—NH—,

R₄ is a hydrogen atom or a group

R₅ and R′₅, which are identical or different, are each a hydrogen atom or a linear, branched or cyclized C₁-C₆ alkyl group,

R₆ is a hydrogen atom or a linear or branched C₁-C₃ alkyl group,

m is a number with a value of 0, 1 or 2,

n is a number with a value of 2, 3 or 4, and

p is a number with a value of 1, 2 or 3; and

(ii) their addition salts.

According to the invention, a process for the preparation of the compounds of formula I and their addition salts is also recommended.

The use of a substance selected from the compounds of formula I and their non-toxic addition salts is also recommended for obtaining a drug intended for use in therapeutics to combat pathological conditions involving bradykinin or its analogs, in particular to combat pain, and especially in the treatment or prevention of pathological conditions associated with inflammatory or painful states.

DETAILED DESCRIPTION OF THE INVENTION

In general formula I of the compounds of the invention, halogen atom is understood as meaning a fluorine, chlorine, bromine or iodine atom, the preferred halogen being the chlorine atom.

C₁-C₃ alkyl group with a linear or branched hydrocarbon chain is understood here as meaning the methyl, ethyl, propyl and 1-methylethyl groups. Linear, branched or cyclized C₁-C₆ alkyl groups are understood as meaning especially the methyl, ethyl, propyl, butyl, pentyl, hexyl, 1-methylethyl, 1-methylpropyl, cyclopentyl and cyclohexyl groups.

In the compound of formula I, the nitrogen heterocycle of the pyrrolidine type carrying the groups COR₃ and R₂ can comprise 1 or 2 asymmetric carbon atoms. According to the invention, these carbon atoms can have the (R,S), R or S configuration; the carbon carrying the group COR₃ will preferably have the S configuration.

“Addition salts” are understood here as meaning the acid addition salts obtained by reacting a compound of formula I with a mineral or organic acid. The preferred mineral acids for salifying a basic compound of formula I are hydrochloric, hydrobromic, phosphoric and sulfuric acids. The preferred organic acids for salifying a basic compound of formula I are methanesulfonic, maleic, fumaric, oxalic, citric and trifluoroacetic acids.

Room temperature (RT) is understood here as meaning a temperature of between 15 and 25° C., and temperature close to RT is understood here as meaning a temperature of between 5 and 35° C.

The process recommended according to the invention for the preparation of the compounds of formula I and their addition salts comprises the steps which consist in:

1) reacting a compound of the formula

in which X and X₁ are each a halogen,

R₂ is a hydrogen atom or an OH group, and

the carbon carrying the group COOCH₃ and the carbon carrying the group R₂, when the latter is not the hydrogen atom, independently of one another have the (R,S), (R) or (S) configuration,

with a compound of the formula

in which:

R₁ is a hydrogen atom or a C₁-C₃ alkyl group, and

Y is an alkali metal such as sodium or potassium,

in an anhydrous solvent, for example dimethylformamide, at a temperature of between 0 and 50° C., for 0.5 to 5 hours, to give a compound of the formula

in which X, R₁ and R₂ are as defined in the starting compounds and the carbon atoms carrying the substituents COOCH₃ and R₂ retain the same configuration as in the compound II above;

2) subjecting the resulting compound IV to alkaline hydrolysis of the ester linkage by reaction with an aqueous solution of a metal hydroxide (especially NaOH) in an inert solvent, especially dimethoxyethane, at a temperature of between 10 and 50° C., for 1 to 30 hours, to give, after acidification, the acid compound of the formula

in which X, R₁ and R₂ are as defined in the compound IV above;

3) reacting the resulting acid V with an alcohol or an amine of the formula

in which:

m is 0, 1 or 2,

n is 2, 3 or 4,

R₆ is a hydrogen atom or a C₁-C₃ alkyl group, and

R₇ is an amino-protecting group, for example a Boc [(1,1-dimethylethoxy)carbonyl] group or, in certain cases, a hydrogen atom,

in a solvent, for example dichloromethane, in the presence of one or more activators, for example 1-hydroxy-7-azabenzotriazole (HOAT) and 1-[3-(dimethylaminopropyl)-3-ethyl]carbodiimide (EDCI) hydrochloride, at a temperature close to room temperature, for 2 to 50 hours, to give a compound of the formula

in which:

X, R₁ and R₂ are as defined above and R′ is one of the following groups:

in which m, n, R₆ and R₇ are as defined above;

4) if necessary, i.e. when R₇ is an amino-protecting group, deprotecting the compound of formula VI thus obtained in the previous step by reacting said compound of formula VI with an acid, for example trifluoroacetic acid or hydrochloric acid, optionally in the presence of a free radical scavenger, for example anisole, and optionally in a solvent, for example ethyl acetate, at a temperature close to room temperature, for 1 to 20 hours, to give the compound of general formula VI described above in which R₇ is a hydrogen atom (corresponding to the compound of formula I in which A is a single bond and R₄ is a hydrogen atom);

5) if necessary, reacting the resulting compound of formula VI in which R₇ is a hydrogen atom with a compound of the formula

R₈—NH—(CH₂)_(p)—COOH

in which p is a number equal to 1, 2 or 3, and

R₈ is an amino-protecting group of the oxycarbonyl type, especially an alkoxycarbonyl group such as Boc [(1,1-dimethylethoxy)carbonyl],

under reaction conditions analogous to those described in step 3 above, to give a compound of the formula

in which X, R₁ and R₂ are as defined above and R″ is a group

in which m, n, p, R₆ and R₈ are as defined above;

6) reacting the compound of formula VII obtained above according to step 5, under conditions analogous to those described in step 4 above, so as to replace the amino-protecting group R₈ with a hydrogen atom to give a compound of the formula

in which X, R₁ and R₂ are as defined above and R is a group

in which m, n and R₆ are as defined above and A is the group —CO—(CH₂)_(p)—NH—, in which p is a number equal to 1, 2 or 3;

7) if necessary, reacting a compound of formula I obtained in one of steps 4 or 6 above, in which A is a single bond or a group

with a compound of the formula

in which R₈ is an amino-protecting group of the oxycarbonyl type, especially an alkoxycarbonyl group such as Boc [(1,1-dimethylethoxy)carbonyl], in a solvent, for example dimethylformamide, in the presence of a base, for example triethylamine, and in the presence of mercuric chloride, at a temperature of between 0 and 30° C., for 1 to 6 hours, to give the compound of the formula

in which R₁, R₂ and X are as defined above and R″ is a group

in which:

A is a single bond or the group —CO—(CH₂)_(p)—NH—, and

n, m, p, R₆ and R₈ are as defined above; and

8) deprotecting the compound of formula VII thus obtained according to step 7, by means of a reaction analogous to that of step 6 above, so as to replace the amino-protecting group R₈ with a hydrogen atom to give a compound of formula I according to the invention in which R₄ is a group —C(═NR₅)NHR′₅ and R₅ and R′₅ are each a hydrogen atom.

In a first variant, step 7 can be carried out as indicated below without effecting the deprotection of step 8:

7a) reacting the hydrochloride of a compound of formula I obtained in one of steps 4 or 6 above with a compound of the formula

R₅—N═C═N—R′₅

in which R₅ and R′₅ are each a linear, branched or cyclized C₁-C₆ alkly group, in an inert solvent, for example acetonitrile, at a temperature close to room temperature, for 4 to 48 hours, to give a compound of formula I according to the invention in which R₅ and R′5 are each a linear, branched or cyclized C₁-C₆ alkyl group and A is a single bond or the group —CO—(CH₂)_(p)—NH—.

In a second variant of step 7, the hydrochloride of a compound of formula VI obtained according to one of steps 4 or 6 above is reacted with a compound of the formula

in which R₈ is an amino-protecting group of the Boc type,

in the presence of an aprotic organic base such as triethylamine, and in the presence of mercuric oxide, in a solvent, for example ethanol, at room temperature, for 5 to 50 hours, to give the compound of formula VII, the structure of which is analogous to that obtained in step 7 above. This compound is then treated by the process described in step 8 above to give the compound of formula I according to the invention in which:

A is a single bond or a group —CO—(CH₂)_(p)—NH—, and

R₄ is the group —C(═NH)NH₂.

Some of the compounds of formulae III and IV, particularly the compounds referred to in claim 3 below, are novel products useful as synthesis intermediates and constitute one of the subjects of the invention.

The invention will be understood more clearly from the Preparatory Examples which follow and from the results of pharmacological tests obtained with some of the compounds according to the invention. In the case of compounds which have an asymmetric carbon in their structure, the absence of a particular indication, or the notation (R,S) [or (D,L) in the case of amino acids], means that the compounds are racemic; in the case of compounds which exhibit chirality, this is indicated immediately after the numbering of the substituent carried by said asymmetric carbon; the symbol (R) or (S) is then used in accordance with the Cahn-Ingold-Prelog rules or, in the case of amino acids, the notation (D) or (L) is used. The nomenclature used in the Examples is that recommended by Chemical Abstracts; thus, after reaction of the acid group with an amine, certain L-proline derivatives may become 2-(S)-pyrrolidinecarboxamide derivatives.

In the experimental section, the “Preparations” relate to the intermediates and the “Examples” relate to the products according to the invention.

The melting points (m.p.) indicated below are generally measured using a Koffler bench and are not corrected, so they represent instantaneous melting points.

PREPARATION I

3-Bromomethyl-2,4dichlorobenzenesulfonyl chloride

85.44 g (0.48 mol) of N-bromosuccinimide and then 200 mg of benzoyl peroxide are added to a solution, at room temperature, of 41.52 g (0.16 mol) of 2,4-dichloro-3-methylbenzenesulfonyl chloride in 150 ml of 1,1,2,2-tetrachloroethane. The reaction mixture is heated at 120° C. for 2 hours. It is cooled and filtered and the filtrate is washed successively with water, with saturated sodium bicarbonate solution and finally with water until the washings are neutral. The organic phase collected from the filtrate is then dried over magnesium sulfate and concentrated. Recrystallization from hexane gives 25.53 g of the expected product in the form of white crystals (yield =47%).

M.p.=90-92° C.

PREPARATION II

3-Chloromethyl-2,4-dichlorobenzenesulfonyl chloride

10 g (0.075 mol) of N-chlorosuccinimide and 30 mg of benzoyl peroxide are added to a solution of 6.5 g (0.025 mol) of 2,4-dichloro-3-methylbenzenesulfonyl chloride in 30 ml of 1,1,2,2-tetrachloroethane at room temperature and under a nitrogen atmosphere. The reaction mixture is heated at 120° C. for 3 hours, cooled to room temperature, poured into water and then extracted with dichloromethane. The organic phase is washed with water, with saturated sodium bicarbonate solution and finally with water until the washings are neutral. It is then dried over magnesium sulfate and concentrated under reduced pressure. Recrystallization from hexane gives 0.85 g of the expected product in the form of white crystals (yield=11.5%).

M.p. 68° C.

PREPARATION III

N-[(3-Bromomethyl-2,4-dichlorophenyl)sulfonyl]-(D,L)-proline methyl ester

27.08 g (0.08 mol) of the compound obtained according to Preparation I are added to a solution of 13.24 g (0.08 mol) of (D,L)-proline methyl ester hydrochloride in 60 ml of dichloromethane. The mixture is cooled to 0° C. and a solution of 23.3 ml (0.16 mol) of triethylamine in 20 ml of dichloromethane is added dropwise. The reaction mixture is then stirred at room temperature for 30 minutes. It is poured into water and extracted with dichloromethane. The organic phase is washed with 1 N hydrochloric acid solution and then with water until the pH is neutral. It is finally dried and concentrated under reduced pressure to give 34.48 g of an oil, which is used directly in the next steps. The product obtained also contains the compound N-[(3-chloromethyl-2,4-dichlorophenyl)sulfonyl]-(D,L)-proline methyl ester originating from a secondary reaction. As this by-product possesses essentially the same reactivity as the brominated derivative, the mixture is used directly without further purification.

PREPARATION IV

N-[(3-Bromomethyl-2,4-dichlorophenyl)sulfonyl]-L-proline methyl ester

The expected product is obtained in the form of an oil by following a procedure analogous to Preparation III, starting from L-proline methyl ester hydrochloride. (The product obtained contains the chlorinated analog originating from a secondary halogen exchange reaction.)

PREPARATION V

N-[(3-Bromomethyl-2,4dichlorophenyl)sulfonyl]-4(trans)-hydroxy-L-proline methyl ester

The expected product is obtained in the form of an oil by following a procedure analogous to Preparation III, starting from 4-(trans)-hydroxy-L-proline methyl ester hydrochloride. (The product obtained contains the chlorinated analog originating from a secondary halogen exchange reaction.)

PREPARATION VI

N-[[3-[(2-Methylquinolin-8-yl)oxymethy]-2,4-dichlorophenyl]sulfonyl]-D,L-proline methyl ester

0.051 g (1.7.10⁻³ mol) of sodium hydride as an 80% suspension in oil is added to a solution of 0.270 g (1.7.10⁻³ mol) of 8-hydroxy-2-methylquinoline in 5 ml of N,N-dimethylformnamide (DMF). After stirring for ten minutes at room temperature, a solution of 0.8 g of the compound obtained according to Preparation III in 2 ml of DMF is added. Stirring is maintained for 2 hours at room temperature. The reaction mixture is diluted with water and extracted with ethyl acetate. The organic phases are washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel using a toluene/ethyl acetate mixture (80/20; v/v) as the eluent. The solid recovered is recrystallized from 15 ml of isopropanol to give 0.7 g of the expected product in the form of a white powder (yield=81%).

M.p.=142° C.

PREPARATION VII

N-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-proline methyl ester

By following a procedure analogous to Preparation VI, starting from the compound obtained according to Preparation IV, the expected product is obtained with a yield of 83% after recrystallization from isopropanol.

M.p.=136° C.

[α]_(D) ²³=+29.4° (c=1.01; CHCl₃)

PREPARATION VIII

N-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-proline methyl ester

By following a procedure analogous to Preparation VI, starting from the compound obtained according to Preparation IV and 2,4-dimethyl-8-hydroxyquinoline, the expected product is obtained with a yield of 72% after recrystallization from isopropanol.

M.p.=138° C.

[α]_(D) ²²=−28° (c=0.5; CHCl₃)

PREPARATION IX

N-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-4-(trans)-hydroxy-L-proline methyl ester

By following a procedure analogous to Preparation VI, starting from the compound obtained according to Preparation V and 2,4-dimethyl-8-hydroxyquinoline, the expected product is obtained with a yield of 44% in the form of a white solid after purification by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (7/3; v/v) as the eluent, followed by crystallization from isopropyl ether.

M.p.=100° C.

[α]_(D) ²¹=−30° (c=0.31; CHCl₃)

PREPARATION X

N-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-D,L-proline

20 ml (20.10⁻³ mol) of 1 N aqueous sodium hydroxide solution are added to a solution of 5.14 g (10.2.10⁻³ mol) of the compound obtained according to Preparation VI in 100 ml of 1,2-dimethoxyethane. The reaction mixture is stirred at 40° C. for 1.5 hours and then at room temperature for 20 hours. The mixture is then concentrated under reduced pressure and the residue is taken up with water and acidified to pH 5 with 1 N hydrochloric acid. After extraction with dichloromethane, the organic phase is washed with water, dried and concentrated under reduced pressure. The resulting solid is recrystallized from 30 ml of isopropanol to give 4.4 g of the expected product in the form of white crystals (yield=87%).

M.p.=120° C.

PREPARATION XI

N-[[3-[(2-Methylquinolin-8yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-proline

The expected product is obtained with a yield of 93% by following a procedure analogous to Preparation X, starting from the compound obtained according to Preparation VII.

M.p.=135° C.

[α]_(D) ²³=−99.3° (c=0.31; CHCl₃)

PREPARATION XII

N-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-L-proline

The expected product is obtained with a yield of 95% by following a procedure analogous to Preparation X starting from the compound obtained according to Preparation VIII.

M.p.=219-220° C.

[α]_(D) ²²=−79.2° (c=0.31; CHCl₃)

PREPARATION XIII

N-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichloropheny]sulfonyl]-4-(trans)-hydroxy-L-proline

A suspension of 0.53 g (0.983.10⁻³ mol) of the compound obtained according to Preparation IX in 35 ml of methanol is prepared, 5 ml of 0.3 N sodium hydroxide solution are added and the reaction mixture is stirred for 18 hours under reflux. It is then concentrated under reduced pressure and the residue is then taken up with water and acidified to pH 5 with 1 N hydrochloric acid. After extraction with dichloromethane, the organic phase is washed with water, dried over magnesium sulfate and then concentrated under reduced pressure to give 490 mg of the expected product in the form of a white solid.

M.p.>260° C.

[α]_(D) ²¹=−55° (c=0.36; CHCl₃)

REPARATION XIV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-(1,1-dimethylethoxycarbonylamino)ethyl]-N-methyl-2-(S)-pyrrolidinecarboxamide

A solution of 0.742 g (1.5.10⁻³ mol) of the acid obtained according to Preparation XI in 10 ml of dichloromethane is prepared and 0.21 g (1.1.10⁻³ mol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI) hydrochloride, 0.15 g (1.1.10⁻³ mol) of 1-hydroxy-7-azabenzotriazole (HOAT) and then 0.261 g (1.5.10⁻³ mol) of N-methyl-N′-(1,1-dimethylethoxycarbonyl)-1,2-ethanediamine are added. The reaction mixture is stirred at room temperature for 20 hours and then concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel using a toluene/isopropanol mixture (95/5; v/v) as the eluent to give 0.61 g of the expected product in the form of a white solid with a yield of 61%.

M.p.=88° C.

[α]_(D) ²²=−4.5° (c=0.2; CH₃OH)

PREPARATION XV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-(1,1-dimethylethoxycarbonylamino)propyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 57% by following a procedure analogous to Preparation XIV, starting from N-(1,1-dimethylethoxycarbonyl)-1,3-propanediamine.

M.p.=78-80° C.

[α]_(D) ²²=−38° (c=0.3; CH₃OH)

PREPARATION XVI

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 20% by following a procedure analogous to Preparation XIV, starting from 1-(1,1-dimethylethoxycarbonyl)-4-(aminomethyl)piperidine.

M.p.=68° C.

[α]_(D) ²²=+38° (c=0.32; CH₃OH)

PREPARATION XVII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 42.3% by following a procedure analogous to Preparation XIV, starting from 1-(1,1-dimethylethoxycarbonyl)-4-aminopiperidine.

M.p.=70-74° C.

[α]_(D) ²²=−27° (c=0.37; CH₃OH)

PREPARATION XVII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid 1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl ester

The expected product is obtained in the form of an oil with a yield of 23.6% by following a procedure analogous to Preparation XIV, starting from 1-(1,1-dimethylethoxycarbonyl)-4-hydroxypiperidine.

[α]_(D) ²²=+22° (c=0.17; CH₃OH)

PREPARATION XIX

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid [1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl-methyl] ester

The expected product is obtained with a yield of 37.6% by following a procedure analogous to Preparation XIV, starting from 1-(1,1-dimethylethoxycarbonyl)-4-hydroxymethylpiperidine.

M.p.=66-68° C.

[α]_(D) ²²=−19° (c=0.28; CH₃OH)

PREPARATION XX

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[(1,1-dimethylethoxycarbonylamino)propyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 74% by following a procedure analogous to Preparation XIV, starting from the compound of Preparation XII and N-(1,1-dimethylethoxycarbonyl)-1,3-propanediamine.

M.p.=80-84° C.

[α]_(D) ²²=−38° (c=0.32; CH₃OH)

PREPARATION XXI

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl]carbonyl]pyrrolidine

The expected product is obtained with a yield of 66% by following a procedure analogous to Preparation XX, starting from 1-(1,1-dimethylethoxycarbonyl)piperazine.

M.p.=100° C.

[α]_(D) ²⁴=−33.3° (c=0.30; CH₃OH)

PREPARATION XXII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4dichlorophenyl]sulfonyl]-2-(S)-[[4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl]carbonyl]-4-(R)-hydroxypyrrolidine

The expected product is obtained with a yield of 72% by following a procedure analogous to Preparation XXI, starting from the compound of Preparation XIII.

M.p.=223° C.

[α]_(D) ²¹=−33° (c=0.34; CHCl₃)

EXAMPLE 1

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[(3,5-dimethylpiperazin-1-yl)carbonyl]pyrrolidine

The expected product is obtained with a yield of 13% by following a procedure analogous to Preparation XIV, starting from an excess of 2,6-dimethylpiperazine.

M.p.=102-106° C.

[α]_(D) ²²=−2° (c=0.3; CHCl₃)

EXAMPLE 2

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[(piperazin-1-yl)carbonyl]pyrrolidine

The expected product is obtained with a yield of 20% by following a procedure analogous to Preparation XIV, starting from an excess of piperazine.

M.p.=164-166° C.

[α]_(D) ²⁴=−1° (c=0.28; CHCl₃)

EXAMPLE 3

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(2-aminoethyl)-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 40.9% by following a procedure analogous to Preparation XIV, starting from an excess of 1,2-ethanediamine.

M.p.=78-80° C.

[α]_(D) ²¹=−58.6° (c=0.35; CHCl₃)

EXAMPLE 4

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(2-aminoethyl)-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 42.7% by following a procedure analogous to Preparation XX, starting from an excess of 1,2-ethanediamine.

M.p.=104-106° C.

[α]_(D) ²¹=−55.2° (c=0.28; CHCl₃)

EXAMPLE 5

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[(piperazin-1-yl)carbonyl]pyrrolidine bistrifluoroacetate

A mixture of 0.6 g (0.885.10⁻³ mol) of the compound obtained according to Preparation XXI and 96 mg (0.885.10⁻³ mol) of anisole is prepared and 3 ml of trifluoroacetic acid are then added at 0° C. The solution is stirred for 3 hours at 0° C. and then overnight at room temperature. After concentration under reduced pressure, the residue is precipitated in anhydrous diethyl ether. The precipitate is separated off, rinsed with ether and dried under vacuum to give 0.64 g of the expected product in the form of a white solid (yield=90%).

M.p.=150° C.

[α]_(D) ²⁴=+12.6° (c=0.31; CH₃OH)

EXAMPLE 6

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-methyl-N-(2-aminoethyl)-2-(S)-pyrrolidinecarboxamide bistrifluoroacetate

The expected product is obtained with a yield of 95% by following a procedure analogous to Example 5, starting from the compound obtained according to Preparation XIV.

M.p.=130° C.

[α]_(D) ²²=+3.2° (c=0.5; CH₃OH)

EXAMPLE 7

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-4-(R)-hydroxy-2-(S)-[(piperazin-1-yl)carbonyl]pyrrolidine bistrifluoroacetate

The expected product is obtained with a yield of 92% by following a procedure analogous to Example 5, starting from the compound obtained according to Preparation XXII.

M.p.=165° C.

[α]_(D) ²³=+19° (c=0.32; CH₃OH)

EXAMPLE 8

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(piperidin-4-yl)-2-(S)-pyrrolidinecarboxamide dihydrochloride

50 ml of a 1.25 N solution of hydrogen chloride in ethyl acetate are prepared and then mixed with 8.25 g (12.17.10⁻³ mol) of the compound obtained according to Preparation XVII. The reaction medium is stirred for 15 hours at room temperature. The precipitate obtained is filtered off, washed with ether and then dried and redissolved in distilled water. After lyophilization of the resulting solution, 7.11 g of the expected product are obtained in the form of a white solid (yield =95%).

M.p.=177° C.

[α]_(D) ²²=−21° (c=0.33; CH₃OH)

EXAMPLE 9

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(3-aminopropyl)-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 68% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XV.

M.p.=158-162° C.

[α]_(D) ²²=−36° (c=0.29; CH₃OH)

EXAMPLE 10

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[(piperidin-4-yl)methyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 59% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XVI.

M.p.=170° C.

[α]_(D) ²²=−27° (c=0.26; CH₃OH)

EXAMPLE 11

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid piperidin-4-yl ester dihydrochloride

The expected product is obtained with a yield of 92% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XVIII.

M.p.=150-154° C.

[α]_(D) ²²=+11° (c=0.3; CH₃OH)

EXAMPLE 12

1-[[3-(2-Methylquinolin-8-yl)oxymethyl]-[2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid [(piperidin-4-yl)methyl] ester dihydrochloride

The expected product is obtained with a yield of 95% by following a procedure analogous to Preparation XXX, starting from the compound obtained according to Preparation XIX.

M.p.=154-158° C.

[α]_(D) ²²=+7° (c=0.31; CH₃OH)

EXAMPLE 13

1-[[3-[(2,4-Dimethylquinolin-8-yl(oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(3-aminopropyl)-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 68% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XX.

M.p.=158-162° C.

[α]_(D) ²²=−36° (c=0.29; CH₃OH)

PREPARATION XXIII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[[(1,1-dimethylethoxycarbonylamino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperazin-1-yl]carbonyl]pyrrolidine

a) A solution of 0.475 g of the compound obtained according to Example 5 is treated with 1 N sodium hydroxide solution in order to bring the pH to a slightly basic value, and extraction is carried out twice with ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated under reduced pressure to give the compound corresponding to Example 5 in the form of the base.

b) A mixture of 0.34 g (0.589.10⁻³ mol) of the compound obtained above, 0.131 g (1.3.10⁻³ mol) of triethylamine and 0.17 g (0.589.10⁻³ mol) of N,N′-bis(1,1-dimethylethoxycarbonyl)thiourea in 10 ml of DMF is prepared. It is cooled to 0° C., 0.18 g (0.65.10⁻³ mol) of mercuric chloride is added and the reaction mixture is then stirred for 3 hours at room temperature. It is then diluted with 60 ml of ethyl acetate and washed with water. The organic phase is dried and then concentrated under reduced pressure. The residue is purified by chromatography on silica gel using a dichloromethane/ethyl acetate mixture (614; v/v) as the eluent to give 0.38 g of the expected product in the form of a white solid (yield 79%).

M.p.=100° C.

[α]_(D) ²⁴=−25° (c=0.29; CH₃OH)

PREPARATION XXIV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperazin-1-yl]carbonyl]pyrrolidine

The expected product is obtained with a yield of 70% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 2.

M.p.=164-168° C.

[α]_(D) ²³=+2° (c=0.26; CH₃OH)

PREPARATION XXV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]-3,5-dimethylpiperazin-1-yl]carbonyl]pyrrolidine

The expected product is obtained with a yield of 53% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 1.

PREPARATION XXVI

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperazin-1-yl]carbonyl]-4-(R)-hydroxypyrrolidine

The expected product is obtained with a yield of 77%, after crystallization from isopropyl ether, by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 7.

M.p.=200° C.

[α]_(D) ²¹=−138° (c=0.33; CHCl₃)

REPARATION XXVII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]-methylamino]ethyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 50% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 3.

PREPARATION XXVIII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]ethyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 51% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 4.

M.p.=114-118° C.

[α]_(D) ²³=−24° (c=0.4; CH₃OH)

PREPARATION XXIX

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]propyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 70% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 13.

M.p.=106-110° C.

[α]_(D) ²²=−20° (c=0.33; CH₃OH)

PREPARATION XXX

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]-methylamino]propyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 30% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 9.

M.p.=116-120° C.

[α]_(D) ²³=−17° (c=0.31; CH₃OH)

PREPARATION XXXI

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]-methylamino]ethyl]-N-methyl-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 68% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 6.

M.p.=95° C.

[α]_(D) ²²=−10.4° (c=0.45; CHCl₃)

PREPARATION XXXII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]-methyl]piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 58% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 10.

M.p.=104-108° C.

[α]_(D) ²²=−32° (c=0.30; CH₃OH)

PREPARATION XXXIII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]-methyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 47.3% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 8.

PREPARATION XXXIV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid [1-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperidin-4-yl] ester

The expected product is obtained with a yield of 80% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 11.

M.p.=75° C.

[α]_(D) ²²=+23° (c=0.25; CH₃OH)

PREPARATION XXXV

1-[[3-[(2-Methylquinolin-8yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid [[1-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperidin-4-yl]methyl] ester

The expected product is obtained with a yield of 57% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 12.

M.p.=74° C.

[α]_(D) ²²=−19° (c=0.29; CH₃OH)

EXAMPLE 14

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-(aminoiminomethyl)piperazin-1-yl]carbonyl]pyrrolidine bistrifluoroacetate

The expected product is obtained by following a procedure analogous to the process for obtaining the compound according to Example 5, starting from the compound of Preparation XXIII. It is then redissolved in pure water, the solution is filtered and the filtrate is lyophilized to give the expected product pure in the form of a cottony white solid (yield =79%).

M.p.=145° C.

[α]_(D) ²⁴=+14° (c =0.34; CH₃OH)

EXAMPLE 15

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-(aminoiminomethyl)piperazin-1-yl]carbonyl]-4-(R)-hydroxypyrrolidine bistrifluoroacetate

The expected product is obtained with a yield of 87% by following a procedure analogous to the process of Example 14, starting from the compound obtained according to Preparation XXVI.

M.p.=165° C.

[α]_(D) ²¹=+39° (c=0.31; CH₃OH)

EXAMPLE 16

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[(aminoiminomethyl)amino]ethyl]-2-(S)-pyrrolidinecarboxamide bistrifluoroacetate

The expected product is obtained with a yield of 52% by following a procedure analogous to Example 14, starting from the compound of Preparation XXVII.

M.p.=138-142° C.

[α]_(D) ²³=−16° (c=0.30; CH₃OH)

EXAMPLE 17

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[(aminoiminomethyl)amino]ethyl]-N-(methyl)-2-(S)-pyrrolidinecarboxamide bistrifluoroacetate

The expected product is obtained with a yield of 88% by following a procedure analogous to Example 14, starting from the compound of Preparation XXXI.

M.p.=137° C.

[α]_(D) ²²=+10.6° (c=0.48; CH₃OH)

EXAMPLE 18

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid [[1-(aminoiminomethyl)piperidin-4-yl]methyl] ester bistrifluoroacetate

The expected product is obtained with a yield of 70% by following a procedure analogous to Example 14, starting from the compound obtained according to Preparation XXXV.

M.p.=126-130° C.

[α]_(D) ²²=−1° (c=0.38; CH₃OH)

EXAMPLE 19

1-[[3-[(2,4-Dimethylquinolin-8yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[(aminoiminomethyl)amino]ethyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 60% by following a procedure analogous to the process for obtaining the compound according to Example 8, starting from the compound obtained according to Preparation XXVIII.

M.p.=170-174° C.

[α]_(D) ²⁴=−39° (c=0.30; CH₃OH)

EXAMPLE 20

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(aminoiminomethyl)amino]propyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 80% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXIX.

M.p.=170-174° C.

[α]_(D) ²⁴=−34° (c=0.29; CH₃OH)

EXAMPLE 21

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[3-[(aminoiminomethyl)amino]propyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 52% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXX.

M.p.=158-160° C.

[α]_(D) ²²=−30° (c =0.31; CH₃OH)

EXAMPLE 22

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-(aminoiminomethyl)piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 95% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXXII.

M.p.=190-192° C.

[α]_(D) ²²=−27° (c=0.35; CH₃OH)

EXAMPLE 23

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(aminoiminomethyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 47% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXXIII.

M.p.=152-156° C.

[α]_(D) ²²=−17° (c=0.30; CH₃OH)

EXAMPLE 24

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-(aminoiminomethyl)piperazin-1-yl]carbonyl]pyrrolidine dihydrochloride

The expected product is obtained with a yield of 60% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXIV.

M.p.=176-180° C.

[α]_(D) ²⁵=+19° (c=0.28; CH₃OH)

EXAMPLE 25

1-[[3-[(2-Methylquinolin-8yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-(aminoiminomethyl)-3,5-dimethylpiperazin-1-yl]carbonyl]pyrrolidine dihydrochloride

The expected product is obtained with a yield of 70% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXV.

M.p.=186-190° C.

[α]_(D) ²²=+21° (c =0.35; CH₃OH)

EXAMPLE 26

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-pyrrolidinecarboxylic acid [1-(aminoiminomethyl)piperidin-4-yl] ester dihydrochloride

The expected product is obtained with a yield of 96% by following a procedure analogous to Example 19, starting from the compound obtained according to Preparation XXXIV.

M.p.=180-184° C.

[α]_(D) ²²=−11° (c=0.30; CH₃OH)

EXAMPLE 27

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[(1-methylethylamino)(1-methylethylimino)methyl]piperazin-1-yl]-carbonyl]pyrrolidine dihydrochloride

a) A solution of 0.24 g (0.426.10⁻³ mol) of the compound obtained according to Example 2 in 5 ml of methanol is prepared and 0.18 ml of an approximately 5 M solution of hydrogen chloride in methanol is added gradually. The mixture is stirred for 1 hour at room temperature and the solvent is then driven off under reduced pressure. The residue is triturated in the presence of ethyl ether and the crystals obtained are filtered off and dried to give 0.24 g of the hydrochloride of the starting material in the form of yellow crystals.

b) A suspension of 0.24 g (0.38.10⁻³ mol) of the compound obtained above in 15 ml of acetonitrile is prepared, 0.24 g (1.9.10⁻³ mol) of diisopropylcarbodiimide is added and the mixture is stirred at room temperature for 24 hours. The solvent is then evaporated off under reduced pressure and the residue is washed several times with hot ethyl acetate. After drying of the crystals under vacuum, 90 mg of the expected product are obtained in the form of white crystals (yield=31%).

M.p.=148-150° C.

[α]_(D) ²²=−1° (c=0.30; CH₃OH)

EXAMPLE 28

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[(cyclohexylamino)(cyclohexylimino)methyl]piperazin-1-yl]carbonyl]-pyrrolidine dihydrochloride

The expected product is obtained with a yield of 26% by following a procedure analogous to the process of Example 27, starting from dicyclohexylcarbodiimide.

M.p.=174-178° C.

[α]_(D) ²²=+9° (c=0.28; CH₃OH)

PREPARATION XXXVI

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[4-(1,1-dimethylethoxycarbonylamino)butyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 70% by following a procedure analogous to Preparation XIV, starting from N-(1,1-dimethylethoxycarbonyl)-1,4-butanediamine.

M.p.=72-74° C.

[α]_(D) ²²=−48° (c=0.29; CHCl₃)

PREPARATION XXXVII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl]ethyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 60% by following a procedure analogous to Preparation XIV, starting from 1-(1,1-dimethylethoxycarbonyl)-4-(2-aminoethyl)piperidine.

M.p.=105° C.

[α]_(D) ²²=−35° (c=0.97; CH₃OH)

PREPARATION XXXVIII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 60% by following a procedure analogous to Preparation XIV, starting from the acid obtained according to Preparation XII and 1-(1,1-dimethylethoxycarbonyl)-4-(aminomethyl)piperidine.

M.p.=80° C.

[α]_(D) ²⁶=−37° (c=1.05; CH₃OH)

PREPARATION XXXIX

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(1,1-dimethylethoxycarbonyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 54% by following a procedure analogous to Preparation XXXVIII, starting from 1-(1,1-dimethylethoxycarbonyl)-4-aminopiperidine.

M.p.=60-64° C.

[α]_(D) ²⁵=−21° (c=1.32; CH₃OH)

EXAMPLE 29

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-(4-aminobutyl)-2-(S)-pyrrolidinecarboxamide dihydrochloride

2.7 g (4.10⁻³ mol) of the compound obtained according to Preparation XXXVI are added to 250 ml of 1 N hydrochloric acid and the mixture is stirred at 45° C. for 2 hours. It is then concentrated under reduced pressure and then diluted with 50 ml of water. The resulting solution is filtered and lyophilized to give the expected product in the form of a white solid with a yield of 95%.

M.p.=164-166° C.

[α]_(D) ²²=−28° (c=0.3; CH₃OH)

EXAMPLE 30

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-(piperidin-4-yl)ethyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 98% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XXXVII.

M.p.=174° C.

[α]_(D) ²²=−30° (c=1.0; CH₃OH)

EXAMPLE 31

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[(piperidin-4-yl)methyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 97% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XXXVIII.

M.p.=195° C.

[α]_(D) ²⁴=−32° (c=1.0; CH₃OH)

EXAMPLE 32

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 85% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XXXIX.

M.p.=184-190° C.

[α]_(D) ²⁵=−14° (c=0.56; CH₃OH)

PREPARATION XL

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[4-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]-methylamino]butyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 50% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 29.

M.p.=82-84° C.

[α]_(D) ²²=−37° (c=0.31; CHCl₃)

PREPARATION XLI

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[1-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperidin-4-yl]ethyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 79% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 30.

M.p.=80° C.

[α]_(D) ²²=−36° (c=1; CH₃OH)

PREPARATION XLII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 75% by following a procedure analogous to Preparation XXIII, starting from the compound obtained according to Example 31.

M.p.=98° C.

[α]_(D) ²²=−31° (c=1.05; CH₃OH)

PREPARATION XLIII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[[(ethyl)(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methyl]piperazin-1-yl]carbonyl]pyrrolidine

8 mg (0.186.10⁻³ mol) of sodium hydride as a 60% suspension in oil are added to a solution of 0.15 g (0.186.10⁻³ mol) of the compound according to Preparation XXIV in 5 ml of dimethylformamide. After stirring for 5 min at room temperature, 58 mg (0.372.10⁻³ mol) of ethyl iodide are added. The mixture is stirred for 20 hours at room temperature and then poured into 100 ml of water. The precipitate formed is filtered off, rinsed with water and dried in an oven under vacuum at 50° C. to give 0.14 g of the expected product in the form of a white solid (yield=90%).

M.p.=95° C.

[α]_(D) ²³=−36° (c=0.32; CH₃OH)

EXAMPLE 33

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[4-[(aminoiminomethyl)amino]butyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 70% by following a procedure analogous to Example 29, starting from the compound obtained according to Preparation XL.

M.p.=148-152° C.

[α]_(D) ²⁴=−31° (c=0.35; CH₃OH)

EXAMPLE 34

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[2-[1-(aminoiminomethyl)piperidin-4-yl]ethyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 82% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLI.

M.p.=165° C.

[α]_(D) ²²=−24.5° (c=1.05; CH₃OH)

EXAMPLE 35

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-(aminoiminomethyl)piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 76% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLII.

M.p.=211° C.

[α]_(D) ²²=−26.5° (c=1.0; CH₃OH)

EXAMPLE 36

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-2-(S)-[[4-[(ethylamino)iminomethyl]piperazin-1-yl]carbonyl]pyrrolidine bistrifluoroacetate

A solution of 0.34 g (0.408.10⁻³ mol) of the compound according to Preparation XLIII in 15 ml of dichloromethane is prepared, 88 mg (0.816.10⁻³ mol) of anisole are then added, the mixture is cooled to 0° C. and 3 ml of trifluoroacetic acid are added. The mixture is stirred for one hour at 0° C. and then overnight at room temperature. The solvents are evaporated off under reduced pressure and the residue is taken up with isopropyl ether. The precipitate formed is filtered off, dried and then redissolved in 5 ml of water and lyophilized to give 0.23 g of the expected product in the form of a white solid (yield=65%).

M.p.=115° C.

[α]_(D) ²³=+10° (c=0.42; CH₃OH)

PREPARATION XLIV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-[4-[(1,1-dimethylethoxycarbonyl)amino]-1-oxobutyl]piperidin-4-yl]methyl]-2-S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 88% by following a procedure analogous to Preparation XIV, starting from the compound obtained according to Example 10 and 4-[(1,1-dimethylethoxycarbonyl)amino]butanoic acid, in the presence of N-methylmorpholine.

M.p.=98° C.

[α]_(D) ²²=−39° (c=1.05; CH₃OH)

PREPARATION XLV

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[2-[(1,1-dimethylethoxycarbonyl)amino]-1-oxoethyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 97% by following a procedure analogous to Preparation XLIV, starting from the compound according to Example 8 and N-(1,1-dimethylethoxycarbonyl)glycine.

M.p.=94° C.

[α]_(D) ²²=−40° (c=1.03; CHCl₃)

PREPARATION XLVI

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[3-[(1,1-dimethylethoxycarbonyl)amino]-1-oxopropyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 97% by following a procedure analogous to Preparation XLIV, starting from the compound according to Example 8 and N-(1,1-dimethylethoxycarbonyl)-β-alanine.

M.p.=100-102° C.

[α]_(D) ²²=−39° (c=1.0; CHCl₂)

PREPARATION XLVII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[4-[(1,1-dimethylethoxycarbonyl)amino]-1-oxobutyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 91% by following a procedure analogous to Preparation XLIV, starting from the compound according to Example 8 and 4-[(1,1-dimethylethoxycarbonyl)amino]butanoic acid.

M.p.=98° C.

[α]_(D) ²²=−39° (c=0.95; CHCl₃)

PREPARATION XLVIII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[3-[(1,1-dimethylethoxycarbonyl)amino]-1-oxopropyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 98% by following a procedure analogous to Preparation XLVI, starting from the compound according to Example 32 and N-(1,1-dimethylethoxycarbonyl)-β-alanine.

M.p.=75-78° C.

[α]_(D) ²²=−53° (c=1.05; CH₃OH)

EXAMPLE 37

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-(4-amino-1-oxobutyl)piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 94% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLIV.

M.p.=151° C.

[α]_(D) ²²=−22.5° (c =0.95; CH₃OH)

EXAMPLE 38

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(2-amino-1-oxoethyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 89% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLV.

M.p.=210° C.

[α]_(D) ²²=−8.6° (c=0.95; CH₃OH)

EXAMPLE 39

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(3-amino-1-oxopropyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 19% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLVI.

M.p.=140° C.

[α]_(D) ²²=−33° (c=0.75; CHCl₃)

EXAMPLE 40

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(4-amino-1-oxobutyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 99% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLVII.

M.p.=174° C.

[α]_(D) ²²=−7.7° (c=1.0; CH₃OH)

EXAMPLE 41

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-(3-amino-1-oxopropyl)piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 98% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation XLVIII.

M.p.=89-91° C.

[α]_(D) ²²=−12.5° (c=1.1; CH₃OH)

PREPARATION IL

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-[4-[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]-1-oxobutylpiperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide

A solution of 1.9 g (2.6.10⁻³ mol) of the compound obtained according to Example 37 in 40 ml of ethanol is prepared and 1.4 ml (10.10⁻³ mol) of triethylamine are added, followed, after stirring for about 5 min, by 0.9 g (3.1.10⁻³ mol) of N,N′-bis(1,1-dimethylethoxycarbonyl)-S-methylisothiourea {or [[[(1,1-dimethylethoxy)carbonyl]amino](methylthio)methylene]carbamic acid 1,1-dimethylethyl ester}; finally, 1.8 g (8.10⁻³ mol) of mercuric oxide are added and the reaction medium is stirred at room temperature for 18 hours. It is filtered and the filtrate is then concentrated under reduced pressure. The residue is purified by chromatography on silica gel using ethyl acetate as the eluent to give 1.7 g of the expected product in the form of white crystals (yield=69%).

M.p.=90° C.

[α]_(D) ²⁰=−32° (c=1.05; CH₃OH)

PREPARATION L

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[2-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]-1-oxoethyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 15% by following a procedure analogous to Preparation IL, starting from the compound obtained according to Example 38.

M.p.=123° C.

[α]_(D) ²²=−32.5° (c=0.9; CHCl₃)

PREPARATION LI

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[3-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]-1-oxopropyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 77% by following a procedure analogous to Preparation IL, starting from the compound obtained according to Example 39.

M.p.=112° C.

[α]_(D) ²²=−23° (c=1.3; CH₃OH)

PREPARATION LII

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[4-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]-1-oxobutyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 74% by following a procedure analogous to Preparation IL, starting from the compound obtained according to Example 40.

M.p.=102-105° C.

[α]_(D) ²⁰=−24° (c=1.05; CH₃OH)

PREPARATION LIII

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[3-[[(1,1-dimethylethoxycarbonyl)amino]-[(1,1-dimethylethoxycarbonyl)imino]methylamino]-1-oxopropyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide

The expected product is obtained with a yield of 86% by following a procedure analogous to Preparation IL, starting from the compound obtained according to Example 41.

M.p.=115-117° C.

[α]_(D) ²²=−22° (c=0.92; CH₃OH)

EXAMPLE 42

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[[1-[4-[(aminoiminomethyl)amino]-1-oxobutyl]piperidin-4-yl]methyl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 75% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation IL.

M.p.=178° C.

[α]_(D) ²²=−19° (c=1.05; CH₃OH)

EXAMPLE 43

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[2-[(aminoiminomethyl)amino]-1-oxoethyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 83% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation L.

M.p.=194° C.

[α]_(D) ²²=−8.7° (c=0.65; CH₃OH)

EXAMPLE 44

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[3-[(aminoiminomethyl)amino]-1-oxopropyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 81% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation LI.

M.p.=170° C.

[α]_(D) ²²=−11.5° (c=1.1; CH₃OH)

EXAMPLE 45

1-[[3-[(2-Methylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[4-[(aminoiminomethyl)amino]-1-oxobutyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 85% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation LII.

M.p.=190° C.

[α]_(D) ²²=−6.1° (c=1.05; CH₃OH)

EXAMPLE 46

1-[[3-[(2,4-Dimethylquinolin-8-yl)oxymethyl]-2,4-dichlorophenyl]sulfonyl]-N-[1-[3-[(aminoiminomethyl)amino]-1-oxopropyl]piperidin-4-yl]-2-(S)-pyrrolidinecarboxamide dihydrochloride

The expected product is obtained with a yield of 74% by following a procedure analogous to Example 8, starting from the compound obtained according to Preparation LIII.

M.p.=174° C.

[α]_(D) ²²=−9.6° (c=1.0; CH₃OH)

The activity of the products according to the invention was evaluated in respect of their ability to bind to the bradykinin receptors. Kinins, of which bradykinin is the main representative, actually form a group of small peptides which make an important contribution to the inflammatory response and therefore appear to be involved in the pathophysiology of inflammatory diseases. Furthermore, bradykinin is one of the most potent analgesics known. Kinins activate two types of receptor, called B₁ and B₂, which belong to the large family of receptors with seven transmembrane domains coupled to the G proteins. In the present invention we describe compounds which bind to the B₂ receptor and thereby block the binding of bradykinin to this receptor.

The following pharmacological test is used: Ileum segments are isolated from male guinea-pigs of the Dunkin-Hartley strain (Iffa Credo, l'Arbresle, France) and ground in the following TES buffer: TES 25 mM, 1,10-phenanthroline 1 mM (pH 6.8), bacitracin 140 μg/ml, BSA 1 g/l. The membranes are then isolated by centrifugation (18,000 rpm; 20 min; 4° C.). The binding studies are carried out in the TES buffer using [³H]-bradykinin (120 pM) and 50 μg of membrane protein per test (final volume 500 μl) with an equilibrium time of 90 min at 20° C. The percentage inhibition of the binding of [³H]-bradykinin is then determined in the presence of one of the test compounds according to the invention at a concentration of 10⁻⁶ M.

The results obtained from these tests (shown as “activity”) are collated in Table I below with reference to the Examples given in the description.

The compounds of the present invention which inhibit the binding of [³H]-bradykinin to the guinea-pig B₂ receptor (see Table I) also bind to the human B₂ receptor cloned and transfected in a stable manner into CHO cells (Chinese Hamster Ovary cells). Thus, in this test, some compounds inhibit the binding of [³]-bradykinin to the B₂ receptor by at least 95% at a concentration of 10 μM.

The compounds of the present invention are useful in the treatment of pain and particularly in the treatment of numerous pathological conditions involving bradykinin or its homologs. These pathological conditions include septic and hemorrhagic shock, anaphylactic reactions, arthrosis, rheumatoid polyarthritis, rhinitis, asthma, inflammatory diseases of the gastrointestinal tract (for example colitis, rectitis, Crohn's disease), pancreatitis, certain carcinomas, hereditary angioedema, migraine, encephalomyelitis, meningitis, cerebrovascular complications (especially those caused by cerebral traumatic shock), certain neurological disorders, vascular inflammatory states (for example atherosclerosis and arteritis of the lower limbs), painful states (for example headache, toothache, menstrual pain), premature uterine contractions, cystitis and burns. The compounds according to the invention can also be useful for the potentiation of antiviral agents.

The compounds of the present invention, which can be used in the form of the free base or in the form of their non-toxic addition salts in association with a physiologically acceptable excipient, will generally be prescribed in therapeutics at doses of about 1 to 1000 mg/day in a form which can be administered orally, by intravenous, intramuscular or subcutaneous injection, transdermally, by means of aerosols or by means of suppositories.

The compounds may also be administered topically, for example in the form of gels or ointments.

The compounds of the present invention are also useful as pharmacological reagents, especially for the study of hormone-receptor interactions. Use as a pharmacological reagent may require a radiolabeled derivative of one of the compounds according to the invention (for example with tritium [³H] or sulfur [³⁵S]) in order to obtain a radioligand intended for conformational studies of the bradykinin B₂ receptor or for binding tests involving this type of receptor, for example for the evaluation of novel compounds which are capable of exhibiting an affinity for the bradykinin B₂ receptor.

According to the invention, a therapeutic composition is recommended which is characterized in that it contains, in association with a physiologically acceptable excipient, at least one active ingredient selected from the group consisting of the compounds of formula I and their non-toxic addition salts.

TABLE I

ACTIVITY Ex. R₁ R₂ R₃ SALT* %  1 H H

— /  2 H H

— 100  3 H H —NH—(CH₂)₂—NH₂ — 100  4 CH₃ H —NH—(CH₂)₂—NH₂ —  5 CH₃ H

tac 100  6 H H —N(CH₃)—(CH₂)₂—NH₂ tac /  7 CH₃ OH

tac /  8 H H

Chl 100  9 H H —NH—(CH₂)₃—NH₂ Chl 100 10 H H

Chl 100 11 H H

Chl / 12 H H

Chl / 13 CH₃ H —NH—(CH₂)₃—NH₂ Chl / 14 CH₃ H

tac  98 15 CH₃ OH

tac 100 16 H H

tac 100 17 H H

tac / 18 H H

tac / 19 CH₃ H

Chl  97 20 CH₃ H

Chl  98 21 H H

Chl / 22 H H

Chl  98 23 H H

Chl 100 24 H H

Chl  98 25 H H

Chl 100 26 H H

Chl / 27 H H

Chl 100 28 H H

Chl / 29 H H —NH—(CH₂)₄—NH₂ ⁻ Chl 30 H H

Chl 31 CH₃ H

Chl 32 CH₃ H

Chl 33 H H

Chl 34 H H

Chl 35 CH₃ H

Chl 36 H H

tac 37 H H

Chl 38 H H

Chl 39 H H

Chl 40 H H

Chl 41 CH₃ H

Chl 42 H H

Chl 43 H H

Chl 44 H H

Chl 45 H H

Chl 46 CH₃ H

Chl Note: *: nature of the salt: “tac” denotes the trifluoroacetic acid salt and “Chl” denotes the hydrochloric acid salt. 

What is claimed is:
 1. An N-Benzenesulfonylpyrrolidine compound, which is selected from the group consisting of (i) compounds of the formula

in which: X is a halogen atom, R₁ is a hydrogen atom or a C₁-C₃ alkyl group having a linear or branched hydrocarbon chain, R₂ is a hydrogen atom or an OH group, and R₃ is a group

in which: A is a single bond or a group —CO—(CH₂)_(p)—NH—, R₄ is a hydrogen atom or a group

R₅ and R′₅, which are identical or different, are each a hydrogen atom or a linear, branched or cyclized C₁-C₆ alkyl group, R₆ is a hydrogen atom or a linear or branched C₁-C₃ alkyl group, m is an integer having a value of 0, 1 or 2, n is an integer having a value of 2, 3 or 4, and p is an integer having a value of 1, 2 or 3; and (ii) their addition salts.
 2. A compound according to claim 1, wherein X is a chlorine atom.
 3. An intermediate compound useful for the preparation of the compounds of formula I which is represented by the formula

in which: R₁ is CH₃, R₂ is H or OH, and R₃ is OH or OCH₃.
 4. A method of treating pathological conditions involving bradykinin, comprising administering to a patient in need of such a treatment a therapeutically effective amount of a compound selected from the group consisting of the compounds of the formula I and non-toxic acid addition salts thereof as claimed in claim
 1. 5. A method according to claim 4 for the treatment of painful or inflammatory disorders comprising administering to a patient in need of such a treatment a therapeutically effective amount of a compound selected from the group consisting of the compounds of the formula I and non-toxic acid addition salts thereof as claimed in claim
 1. 6. A pharmaceutical composition comprising a physiologically acceptable excipient and at least one active ingredient selected from the group consisting of the compounds of formula I and non-toxic addition salts thereof as claimed in claim
 1. 7. A method for preparing a compound of the formula I as claimed in claim 1, wherein R₃ is a group

A is a single bond or a group —CO—(CH₂)_(p)—NH—, R₄ is a group

R₅ and R′₅ are each a hydrogen atom, R₆ is a hydrogen atom or a linear or branched C₁-C₃ alkyl group, m is an integer having a value of 0, 1 or 2, n is an integer having a value of 2, 3 or 4, and p is an integer having a value of 1, 2 or 3, said method comprising: 1) reacting a compound of the formula

in which X and X₁ are each a halogen atom, R₂ is a hydrogen atom or an OH group, and the carbon atom carrying the group COOCH₃ and the carbon atom carrying a group R₂ different from H are independently of the (R,S), (R) or (S) configuration, with a compound of the formula

in which: R₁ is a hydrogen atom or a C₁-C₃ alkyl group, and Y is an alkali metal, in an anhydrous solvent, at a temperature of between 0 and 50° C., for 0.5 to 5 hours, to give a compound of the formula

in which X, R₁ and R₂ are as defined above and the carbon atoms carrying the substituents COOCH₃ and R₂ each retain the same configuration as in the above compound of the formula II; 2) subjecting the resulting compound of the formula IV to an alkaline hydrolysis reaction with an aqueous solution of a metal hydroxide in an inert solvent, at a temperature of between 10 and 50° C., for 1 to 30 hours, to give the acid compound of the formula

in which X, R₁ and R₂ are as defined above; 3) reacting the resulting acid of the formula V with an alcohol or an amine compound of the formula

in which: m is 0, 1 or 2, n is 2, 3 or 4, R₆ is a hydrogen atom or a C₁-C₃ alkyl group, and R₇ is an amino-protecting group or a hydrogen atom, in a solvent, in the presence of at least one activator, at a temperature close to room temperature, for 2 to 50 hours, to give a compound of the formula

in which: X, R₁ and R₂ are as defined above and R′ is a group:

in which m, n, R₆ and R₇ are as defined above; and 4) optionally, when R₇ is an amino-protecting group, deprotecting the compound of the formula VI thus obtained with an acid, to give a compound of the formula VI in which R₇ is a hydrogen atom and which corresponds to the compound of formula I in which A is a single bond and R₄ is a hydrogen atom), 5) reacting the compound of formula VI obtained according to step 3) or 4) and in which R₇ is H with a compound of the formula R₈—NH—(CH₂)_(p)—COOH in which p is a number equal to 1, 2 or 3, and R₈ is an amino-protecting group, in a solvent, in the presence of at least one activator, at a temperature close to room temperature, for 2 to 50 hours, to give a compound of the formula

in which X, R₁ and R₂ are as defined above and R″ is a group

in which m, n, p, R₆ and R₈ are as defined above; 6) reacting the compound of the formula VII thus obtained with an acid for replacing the amino-protecting group R₈ with a hydrogen atom in order to give a compound of the formula

in which X, R₁ and R₂ are as defined above and R₃ is a group

in which m, n and R₆ are as defined above and A is the group —CO—(CH₂)_(p)—NH—, in which p is a number equal to 1, 2 or 3, 7) reacting a compound of the formula VI obtained according to step 3) or 4) above, in which A is a single bond and R₇ is H, or a compound of the formula I obtained according to step 6) above in which A is a group —CO—(CH₂)_(p)—NH—, with a compound of the formula

in which R₈ is an amino-protecting group of the oxycarbonyl type, in a solvent, in the presence of a base and in the presence of mercuric chloride, at a temperature of between 0 and 30° C., for 1 to 6 hours, to give the compound of the formula

in which R₁, R₂ and X are as defined above and R″ is a group

in which: A is a single bond or the group —CO—(CH₂)_(p), —NH—, and n, m, p, R₆ and R₈ are as defined above; and 8) deprotecting the compound of formula VII thus obtained for replacing the amino-protecting group R₈ with a hydrogen atom in order to give a compound of the formula I in which R₄ is a group —C(═NR₅)NHR′₅ and R₅ and R′₅ are each a hydrogen atom. 